Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 39, Pages 19665-19674Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1907631116
Keywords
glpK; Mycobacterium tuberculosis; reversible drug tolerance; phase variation; small colony variant
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Funding
- National Institute of Allergy and Infectious Diseases [U19AI11276, T32AI125185, R01AI111967]
- Singapore Ministry of Health's National Medical Research Council under its Translational and Clinical Research Flagship Grant [NMRC/TCR/011-NUHS/2014]
- Center Grant 'MINE' Core, Singapore Programme of Research Investigating New Approaches to Treatment of Tuberculosis (SPRINT-TB) [4 BSL-3 NMRC/CG/013/2013]
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The length and complexity of tuberculosis (TB) therapy, as well as the propensity of Mycobacterium tuberculosis to develop drug resistance, are major barriers to global TB control efforts. M. tuberculosis is known to have the ability to enter into a drug-tolerant state, which may explain many of these impediments to TB treatment. We have identified a mechanism of genetically encoded but rapidly reversible drug tolerance in M. tuberculosis caused by transient frameshift mutations in a homopolymeric tract (HT) of 7 cytosines (7C) in the glpK gene. Inactivating frameshift mutations associated with the 7C HT in glpK produce small colonies that exhibit heritable multidrug increases in minimal inhibitory concentrations and decreases in drug-dependent killing; however, reversion back to a fully drug-susceptible large-colony phenotype occurs rapidly through the introduction of additional insertions or deletions in the same glpK HT region. These reversible frameshift mutations in the 7C HT of M. tuberculosis glpK occur in clinical isolates, accumulate in M. tuberculosis-infected mice with further accumulation during drug treatment, and exhibit a reversible transcriptional profile including induction of dosR and sigH and repression of kstR regulons, similar to that observed in other in vitro models of M. tuberculosis tolerance. These results suggest that GlpK phase variation may contribute to drug tolerance, treatment failure, and relapse in human TB. Drugs effective against phase-variant M. tuberculosis may hasten TB treatment and improve cure rates.
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